Novel synthesis of primary arylamides from aryl methyl ketone oxidations using iodine in aqueous ammonia

Article abstract of DOI:10.1590/S0103-50532010000500019

Primary arylamides were obtained when several aryl methyl ketones were treated with iodine in aqueous ammonia at room temperature in goods yields.

Full text of DOI:10.1590/S0103-50532010000500019

J. Braz. Chem. Soc., Vol. 21, No. 5, 905-908, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Novel Synthesis of Primary Arylamides from Aryl Methyl Ketone Oxidations
using Iodine in Aqueous Ammonia
Norma A. Angeles, Felipe Villavicencio, Carlos Guadarrama, David Corona and
Erick Cuevas-Yañez*
Centro de Investigación en Química Sustentable UAEM-UNAM, Facultad de Química, Universidad
Autónoma del Estado de México, Carretera Toluca-Atlacomulco Km 14.5 and Paseo Colón esq.
Paseo Tollocan, 50120 Toluca, Mexico
Primary arylamides were obtained when several aryl methyl ketones were treated with iodine
in aqueous ammonia at room temperature in goods yields.
Arilamidas primárias foram obtidas em bons rendimentos quando diversas arilmetilcetonas
foram tratadas com iodo em amônia aquosa a temperatura ambiente.
Keywords: amide, methyl ketone, iodine, ammonia, oxidation
Introduction
with other previous haloform reaction reports12-16 to the
synthesis of primary amides from methyl ketones. This
report describes our successful endeavors in this area.
In a model study, acetophenone was treated with an
excess of iodine (3 molar equivalents) in aqueous ammonia
and THF as cosolvent. After 1 h, iodoform was separated
and the product was extracted. Purification by crystallization
afforded benzamide in 85% yield (Scheme 1).
In order to explore the reaction scope, several aryl
and heteroaryl methyl ketones were reacted under similar
conditions (see Table 1, Scheme 2). In general, the
results showed that amides were the preferred products.
It is noteworthy that ammonia concentration plays an
important role, because the reaction is carried out only
in a concentrated ammonium hydroxide solution, and at
lower ammonia concentrations, the yields decreased or
the amide is not formed, and only the starting material was
isolated (Table 2).
The amide group has a special importance in chemistry
and biochemistry, since this functional group is the frame
of several biological and pharmaceutical products and it
is a point of departure en route to many natural products.1
Currently, one employed method to prepare aryl and
heteroaryl amides involves the haloform cleavage reaction
of trihalo acetyl derivatives.2-5 However, these procedures
require anhydrous conditions and, in some cases, expensive
reagents such as trichloroacetyl chloride for preparing the
trichloroketone starting material.6-7 In addition, the use of
water is preferred in environmental friendly procedures,
which makes the chemical processes economical.8 These
precedents motivated us to explore alternative routes to
prepare amides from less expensive materials using mild
conditions. In connection with other synthetic studies, we
were attracted by the reports of Fang9-10 and Talukdar11
about the transformation of aldehydes to nitriles and
amides, and we decided to apply these reactions in addition
The mechanism proposed for this reaction involves
the triiodo methyl ketone formation, with the subsequent
O
O
I2
CH3
NH2
CHI3
+
THF, NH4OH
Scheme 1. Reaction of acetophenone with iodine in aqueous concentrated ammonia.
*e-mail: ecuevasy@uaemex.mx

906
Novel Synthesis of Primary Arylamides from Aryl Methyl Ketone Oxidations
J. Braz. Chem. Soc.
O
O
I2
R
CH3
R
NH2
CHI3
+
THF, NH4OH
Scheme 2. General reaction of methyl ketones with iodine in aqueous concentrated ammonia.
Table 1. Amides derived from diverse methyl ketones, iodine and ammonia
Entry
Methyl ketone
acetophenone
Amide
Reaction time (h)
mp (oC)
127
mp lit. (oC)
Yield (%)
1
2
3
4
5
6
7
8
benzamide
1
1
12821
13722
85
95
92
90
94
90
83
50
4-methylacetophenone
2-methylacetophenone
4-chloroacetophenone
4-fluoroacetophenone
4-aminoacetophenone
4-methoxyacetophenone
3-acetylthiophene
4-methylbenzamide
2-methylbenzamide
4-chlorobenzamide
4-fluorobenzamide
4-aminobenzamide
4-methoxybenzamide
137
1
140
141-14223
172-17624
152-15324
181-18325
162-163 26
-
0.5
1
175
152
24
24
24
181
162
thiophene-3-carboxylic
acid amide
115
9
1-methyl-3-acetylpyrrole
1-methylpyrrole-3-carboxylic
acid amide
24
140
-
63
10
11
12
13
2-acetylfuran
2-acetylpyridine
3-acetylpyridine
4-acetylpyridine
furamide
12
12
12
12
142
109
129
157
142-14327
108-109 28
128-131 28
15712
82
73
69
49
pyridine-2-carboxylic acid amide
pyridine-3-carboxylic acid amide
pyridine-4-carboxylic acid amide
Table 2. Effect of ammonia concentration in benzamide yield from
acetophenone
On the other hand, this process represents a new variant
of the Haller-Bauer reaction,17-19 which allows the direct
conversion of nonenolizable ketones to primary amides,
with the advantage that strong bases such as sodium amide
are not required.
Ammonia
Reaction time (h)
Yield (%)
Concentration (%)
28
25
20
15
1
3
85
75
50
0
Conclusions
8
24
In conclusion, the appropriately constituted methyl
ketonesareefficientlyconvertedintoprimaryamidesthrough
a simple and mild method. In addition, the procedure is
economic and environmentally benign. These elements
suggest that this route will enjoy widespread application.
ammonia substitution (Scheme 3). Alternatively, enamine
formation and subsequent iodination can also explain amide
formation. At the moment, our group is investigating the
mechanistic details of this reaction.
O
O
2NH3
2I2
O
O
NH3
I2
R
CH2I
-CHI3
R
CI3
R
NH2
R
CH3
NH3
NH3
NH2
CH2
2NH3
2I2
NH
CI3
NH
CH3
NH
NH
I2
R
R
R
R
CH2I
R
OH
OH
Scheme 3. Mechanism of amide formation from methyl ketones and I2-NH3.

Vol. 21, No. 5, 2010
Angeles et al.
907
Experimental
2-Methylbenzamide
Yield 92%, mp 140 °C (MeOH). IR (KBr) nmax/cm-1:
3343, 3163, 1667. 1H NMR (300 MHz, CDCl3) d 2.48 (s,
3H), 5.88 (s, 1H), 6.27 (S, 1H) 7.24-7.46 (m, 4H). 13C MNR
(75 MHz, CDCl3) d 19.9, 125.7, 126.9, 130.2, 131.1, 135.1,
136.3, 171.2. MS m/z (%) 135 [M]+ (65), 119 [M-NH2]+
(100), 91 [M-CONH2]+ (77).
The starting materials were purchased from Aldrich
Chemical Co. and were used without further purification.
Solvents were distilled before use. Silica plates of 0.20 mm
thickness were used for thin layer chromatography.
Melting points were determined with a Fisher-Johns
melting point apparatus and they are uncorrected. 1H and
13C NMR spectra were recorded using a Bruker AVANCE
300, the chemical shifts (d) are given in ppm relative to
TMS as internal standard (0.00). For analytical purposes
the mass spectra were recorded on a JEOL JMS-5X 10217
4-Chlorobenzamide
Yield 90%, mp 175 °C (MeOH). IR (KBr) nmax/cm-1:
3343, 3162, 1666. 1H NMR (300 MHz, CDCl3) d 5.94 (s,
2H) 7.41 (d, 2H, J 8.6 Hz), 7.95 (d, 2H, J 8.6 Hz). 13C NMR
(75 MHz, CDCl3) d 128.9, 128.9, 129.3, 129.3, 132.5,
138.0, 166.9. MS m/z (%) 155 [M]+ (65), 139 [M-NH2]+
(100), 111 [M-CONH2]+ (45).
o
in the EI mode, 70 eV, 200 C via direct inlet probe.
Only the molecular and parent ions (m/z) are reported.
IR spectra were recorded on a Nicolet Magna 55-X FT
instrument.
4-Fluorobenzamide
Synthesis of amides from methyl ketones: CAUTION!
Although we did not have any incidents by handling,
it is known that iodine reacts with ammonia under certain
conditions to generate nitrogen triiodide monoamine
Yield 94%, mp 152 °C (CH2Cl2). IR (KBr) nmax/cm-1:
3326, 3150, 1640. 1H NMR (300 MHz, CDCl3) d 5.94 (s,
2H), 7.35 (d, 2H, J 8.3 Hz), 7.92 (d, 2H, J 8.3 Hz). 13C
NMR (75 MHz, CDCl3) d 115.6, 115.6, 129.9, 129.9, 131.4,
164.7, 167.9 MS m/z (%) 155 [M]+ (65), 139 [M-NH2]+
(100), 111 [M-CONH2]+ (45).
•
(NI3 NH3). The dry powder explodes readily by mechanical
shock, heat or irradiation.20
Typical procedure
4-Aminobenzamide
o
Iodine (0.76 g, 3 mmol) was added to a solution of the
appropriate ketone (1 mmol) in 28% aqueous ammonia
(10 mL) and THF (1 mL). The mixture was stirred for 1 h
at room temperature. The dark solution became colorless
and 10% Na2S2O3 (1 mL) was added. Iodoform was filtered,
the product was extracted with AcOEt (3 × 20 mL). The
organic phase was washed, dried over Na2SO4, and the
solvent was evaporated in vacuo. The final product was
purified by crystallization.
Yield 90%, mp 181 C (MeOH). IR (KBr) nmax/cm-1:
3343, 3163, 1667. 1H NMR (300 MHz, CDCl3) d 5.45 (s,
2H), 6.52 (d, 2H, J 8.76 Hz), 6.73 (s,1H), 7.44 (s, 1H),
7.58 (d, 2H, J 8.76 Hz). 13C NMR (75 MHz, CDCl3) d
112.4, 112.4, 120.9, 128.9, 128.9, 151.4, 168.1. MS m/z
(%) 136 [M]+ (80), 120 [M-NH2]+ (100), 92 [M-CONH2]+
(30).
4-Methoxybenzamide
Yield 83%, mp 162 °C (MeOH). IR (KBr) nmax/cm-1:
3308, 3172, 1617. 1H NMR (300 MHz, CDCl3) d 3.89 (s,
3H), 6.98 (d, 2H, J 8.7 Hz), 7.44 (s, 2H), 7.90 (d, 2H, J
8.7 Hz). 13C NMR (75 MHz, CDCl3) d 56.0, 114.2, 114.2,
127.0, 129.9, 129.9, 163.4, 169.7. MS m/z (%) 151 [M]+
(60), 135 [M-NH2]+ (100).
Benzamide
Yield 85%, mp 127 °C (MeOH). IR (KBr) nmax/cm-1:
3344, 3162, 1667. 1H NMR (300 MHz, CDCl3) d 6.0 (d,
2H), 7.47 (m, 2H), 7.52 (m, 1H), 7.82 (m, 2H). 13C NMR
(75 MHz, CDCl3) d 127.3, 127.3, 128.6, 128.6, 130.2,
132.2, 169.0. MS [EI+] m/z (RI%), (M)+ (10), 120 [M-H]+
(75), 105 [M-NH2]+ (83), 77 [M-CONH2]+ (100).
Thiophene-3-carboxylic acid amide
Yield 50%, mp 115 °C (MeOH). IR (KBr) nmax/cm-1:
1
4-Methylbenzamide
3343, 3163, 1667. H NMR (300 MHz, CDCl3) d 7.33
Yield 95%, mp 137 °C (MeOH). IR (KBr) nmax/cm-1:
3343, 3163, 1667. 1H NMR (300 MHz, CDCl3) d 2.40 (s,
3H), 6.08 (s, 2H), 7.22 (d, 2H, J 8.6 Hz), 7.69 (d, 2H, J
8.2 Hz). 13C NMR (75 MHz, CDCl3) d 21.4, 127.3, 127.3,
129.2, 129.2, 130.9, 142.5, 169.4. MS m/z (%) 135 [M]+
(65), 119 [M-NH2]+ (100), 91 [M-CONH2]+ (65).
(dd, 1H, J1 0.9 Hz, J2 4.8 Hz), 7.53 (dd, 1H, J1 0.9 Hz, J2
4.8 Hz), 8.10 (dd, 1H, J1 0.9 Hz, J2 2.7 Hz). 13C NMR (75
MHz, CDCl3) d 125.9, 126.9, 129.4, 136.7, 164.9. MS m/z
(%) 127 [M]+ (90), 111 [M-NH2]+ (100), 83 [M-CONH2]+
(30). HRMS (FAB+): for C6H9NOS Calc. 128.0170; Found
128.0173.

908
Novel Synthesis of Primary Arylamides from Aryl Methyl Ketone Oxidations
J. Braz. Chem. Soc.
1-Methylpyrrole-3-carboxylic acid amide
2. Hassinger, H. L.; Soll, R. M.; Gribble, G. W.; Tetrahedron Lett.
1998, 39, 3095.
Yield 63%, mp 140 °C (MeOH). IR (KBr) nmax/cm-1:
3342, 3165, 1668. 1H NMR (300 MHz, CDCl3) d 3.68 (s,
3H), 5.65 (s, 2H), 6.57 (m, 2H), 7.22 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 36.5, 109.4, 123.3, 126.0, 126.8,
172.8. MS m/z (%) 124 [M]+ (30), 108 [M-NH2]+ (100),
80 [M-CONH2]+ (20). HRMS (FAB+): for C6H9N2O Calc.
125.0175; Found 125.0177.
3. Jiang, B.; Liu, J. F.; Zhao, S.Y.; J. Org. Chem. 2003, 68, 2376.
4. Kaiserman, J. A.; Gross, M.; Ge, Y.; White, S.; Hu, W.; Duan,
J. X.; Baird, E. E.; Johnson, K. W.; Tanaka, R. D.; Moser, H.
E.; Buerli, R. W.; J. Med. Chem. 2003, 46, 3914.
5. Mamidyala, S. K.; Firestine, S. M.; Tetrahedron Lett. 2006, 47,
7431.
6. Banwell, M. G.; Bray, A. M.; Willis, A. C.; Wong, D. A.; New
J. Chem. 1999, 23, 687.
Furamide
Yield 82%, mp 142 °C (MeOH). IR (KBr) nmax/cm-1:
3361, 3123, 1620. 1H NMR (300 MHz, CDCl3) d 5.25 (s,
2H), 6.52 (d, 1H, J 3.6 Hz), 7.15 (d, 1H, J 3.6 Hz), 7.60 (m,
1H). 13C NMR (75 MHz, CDCl3) d 110.8, 121.3, 144.6,
147.5, 162.2. MS m/z (%) 111 [M]+ (80), 95 [M-NH2]+ (100).
7. Bando, T.; Narita, A.; Saito, I.; Sugiyama, H.; J. Am. Chem.
Soc. 2003, 125, 3471.
8. Lindström, U. M.; Chem. Rev. 2002, 102, 2751.
9. Shie, J. J.; Fang, J. M.; J. Org. Chem. 2007, 72, 3141.
10. Shie, J. J.; Fang, J. M.; J. Org. Chem. 2003, 68, 1158.
11. Talukdar, S.; Hsu, J. L.; Chou, T. C.; Fang, J. M.; Tetrahedron
Lett. 2001, 42, 1103.
Pyridine-2-carboxylic acid amide
Yield 72%, mp 109 °C (MeOH). IR (KBr) nmax/cm-1:
3343, 3163, 1660. 1H NMR (300 MHz, CDCl3) d 7.04 (s,
1H), 7.45 (m, 1H), 7.86 (m, 1H), 8.00 (s, 1H), 8.22 (m, 1H),
8.56 (m, 1H). 13C NMR (75 MHz, CDCl3) d 122.3, 126.3,
137.2, 148.2, 149.6, 167.3. MS m/z (%): 122 [M]+ (30), 89
[M-NH2]+ (100%) , 92 [M-CONH2]+ (30%).
12. Jiménez, O.; Bosch, P.; Guerrero, A.; J. Org. Chem. 2005, 70,
10883.
13. Olivella S.; Solé A.; Jimenez O.; Bosch P.; Guerrero A.; J. Am.
Chem. Soc. 2005, 127, 2620.
14. Levin D.; Kaszynski, P.; Mich, l. J.; Organic Syntheses, Coll.
Vol. X, 2004, 86.
15. Zucco, C.; Lima, C. F.; Rezende, M. C.; Vianna, S. F.; Nome
F.; J. Org. Chem. 1987, 52, 5356.
Pyridine-3-carboxylic acid amide
Yield 69%, mp 129 °C (MeOH). IR (KBr) nmax/cm-1:
3343, 3163, 1660. 1H NMR (300 MHz, CDCl3) d 7.04 (s,
1H), 7.45 (m, 1H), 8.07 (s, 1H), 8.28 (m, 1H), 8.75 (m, 1H),
9.18 (s, 1H). 13C NMR (75 MHz, CDCl3) d 122.4, 128.8,
134.8, 148.2, 151.0, 166.8. MS m/z (%) 122 [M]+ (100),
106 [M-NH2]+ (60%), 78 [M-CONH2]+ (70%).
16. Staunton, J.; Eisenbraun, J.; Organic Syntheses, Coll. Vol. V,
1973; p. 8.
17. Ishihara, K.; Yano, T.; Org. Lett. 2004, 6, 1983.
18. Paquette, L. A.; Gilday, J. P.; Ra, S. C.; Hoppe, M.; J. Org.
Chem. 1988, 53, 704.
19. Walborsky, H. M.; Allen, L. E.; Traenckner, H. J.; Powers, E.
J.; J. Org. Chem. 1971, 36, 2937.
Pyridine-4-carboxylic acid amide
20. Roesky, H. W.; Möckel, K.; Chemical Curiosities, VCH:
Weinheim, 1996, p. 292.
Yield 49%, mp 157 °C (MeOH). IR (KBr) nmax/cm-1:
3343, 3161, 1667. 1H NMR (300 MHz, CDCl3) d 7.22 (s,
1H), 7.82 (d, 2H, J 5.4 Hz), 8.12 (s, 1H), 8.73 (d, 2H, J
5.4 Hz). 13C NMR (75 MHz, CDCl3) d 121.1, 121.1, 140.7,
149.6, 149.6, 167.0. MS m/z (%) 122 [M]+ (100), 106 [M-
NH2]+ (40%), 78 [M-CONH2]+ (55%).
21. McMaster, L.; Langreck, F. B.; J. Am. Chem. Soc. 1917, 39,
103.
22. Feiring, A. E.; J. Org. Chem. 1976, 41,148.
23. Hartman, W. W.; Smith, L. A.; Organic Syntheses, Coll. Vol. II,
1943; p. 586.
24. Joshi, K. C.; Giri, S.; J. Indian Chem. Soc. 1960, 37, 423.
25. Prajapati, D.; Bora, H. N.; Sandhu, J. S.; Ghosh, A. C.; Synth.
Commun. 1995, 25, 4025.
Acknowledgments
Financial support from PROMEP-SEP is gratefully
acknowledged. The authors would like to thank Rocío
Patiño, Angeles Peña, Elizabeth Huerta, Javier Pérez and
Luis Velasco (IQ-UNAM) for the technical support.
26. Chattopadhyaya, J. B.; Rao, A. V. R.; Tetrahedron 1974, 30,
2899.
27. Peng, Y.; Song, G.; Org. Prep. Proced. Int. 2002, 34, 95.
28. Sakai, K.; Ito, T.; Watanabe, K.; Bull. Chem. Soc. Jpn. 1967,
40, 1660.
References
Received: July 14, 2009
1. Reimann,J.E;Byerrum,R.U.InTheChemistryofAmides;Zabicky,
Web Release Date: March 1, 2010
J., Patai, S., eds.; Interscience Publishers: London, 1970, p. 601.